Anti-Inflammatory Lipid Mediators in Asthma

 描述(申请人提供)：依赖氧化还原(Redox)的翻译后修饰介导的细胞信号作用包括半胱氨酸的氧化、谷胱甘肽基化、S亚硝化和烷基化。这些反应将代谢和炎症状态与细胞和器官功能的变化密切联系在一起，因为许多介导代谢和炎症反应的酶、受体和转录调节蛋白含有功能显著的高活性半胱氨酸硫醇。特别关注由一氧化氮(NO)、亚硝酸盐(NO2-)、硝酸盐(NO3-)和次级氮氧化物(NO2-)介导的反应，以及它们通过脂肪酸硝化反应诱导的独特的氧化还原信号反应。内源性产生的各种氮氧化物的性质和数量取决于炎症状态、饮食、酸性微环境和NO3-还原进入唾液的细菌种群。这些产品中的许多都是化学反应的，并产生蛋白质无中心络合物、蛋白质半胱氨酸-一氧化氮加合物(RSNO)和研究计划中的亲电脂肪酸硝基烯烃(NO2-FA)，它容易并可逆地烷基化敏感的蛋白质硫醇。NO2-FAs的cGMP非依赖性多效性信号作用诱导适应性组织反应，包括脂肪因子和细胞因子表达的有益变化，胰岛素敏感性的恢复和呼吸道过度活动的减弱。这促使我们假设，促进硝基脂肪酸信号转导可以减轻代谢综合征诱发的高血压及其肺部并发症。为了测试这一概念，将通过进行机械揭示的模型系统研究和盲法交叉设计第二阶段临床研究来评估降低风险的药物策略：目的1-确定肥胖小鼠呼吸道多动时NO2-FA加成的位置，并确定口服NO2-FA的生化和生理反应。目的#2-评价口服NO2-FA，10-硝基-十八碳-9-烯酸(NO2-OA)对肥胖哮喘患者的临床疗效。我们将确定NO2-FA诱导的呼吸道多动(AHR)肥胖小鼠肺中PTMS的关键位置，并确定这如何影响氧化还原敏感转录因子(TF)功能、基因表达谱和关键酶靶标的活性。目前的数据支持NO2-FA介导的PTMS在小鼠肺部炎症和AHR模型中促进有益的反应。NO2-FA的静脉和口服制剂都经过了广泛的临床前毒理学和药代动力学评估，并正在进行FDA批准的人类第一阶段测试。肥胖哮喘患者对NO2-FA的生理和生化反应将进行盲法、安慰剂对照交叉研究。这些对NO2-FA的反应预计比许多单一靶点的哮喘药物更有效，因为在这种复杂的炎症表型中，NO2-FA的多效性抗炎信号作用有望引起药理学上的共鸣，而不是音符。

 DESCRIPTION (provided by applicant): Cell signaling actions mediated by reduction-oxidation (redox)-dependent post-translational modifications include the oxidation, glutathionylation, S-nitrosation, and alkylation of cysteine. These reactions intimately link metabolic and inflammatory status with changes in cell and organ function, since many enzymes, receptors and transcriptional regulatory proteins mediating metabolic and inflammatory responses contain functionally- significant hyperactive cysteine thiols. Particular focus is being placed on reaction mediated by nitric oxide (NO), nitrite (NO2-) and nitrate (NO3-) and secondary nitrogen oxides and the unique redox signaling responses they induce via fatty acid nitration reactions. The nature and amounts of various nitrogen oxides generated endogenously are dependent on inflammatory status, diet, acidic microenvironments and NO3--reducing enter salivary bacterial populations. Many of these products are chemically-reactive and generate protein NO- home complexes, protein Cys-NO adducts (RSNO) and in the research plan, electrophilic fatty acid nitroalkenes (NO2-FA) that readily and reversibly alkylate susceptible protein thiols. The cGMP-independent pleiotropic signaling actions of NO2-FAs induce adaptive tissue responses that include beneficial shifts in adipokine and cytokine expression, restoration of insulin sensitivity and the attenuation of airway hyperactivity. This motivated us to hypothesize that the promotion of nitro-fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. To test this concept, a de- risked drug strategy will be evaluated by pursuing both mechanistically-revealing model system studies and a blinded crossover design Phase 2 clinical study: Aim #1 - Identify the sites of NO2-FA adduction in the lung tissue of obese mice with airway hyperactivity and define the biochemical and physiological responses to oral NO2-FA administration. Aim #2 - Evaluate the clinical responses of obese asthmatic patients to the orally-administered NO2-FA, 10-nitro-octadeca-9-enoic acid (NO2-OA). We will identify key sites of NO2-FA-induced PTMs in the lungs of obese mice with airway hyperactivity (AHR) and define how this affects redox-sensitive transcription factor (TF) function, gene expression profiles and activities of critical enzyme targets. Current data support that NO2-FA-mediated PTMs promote salutary responses in murine models of pulmonary inflammation and AHR. Both IV and oral formulations of NO2-FA have undergone extensive preclinical toxicology and pharmacokinetics evaluation and are in FDA-approved Phase 1 testing in humans. The physiological and biochemical responses of obese asthmatics to NO2-FA will be studied in a blinded, placebo-controlled crossover study. These responses to NO2-FA are anticipated to be more efficacious than many single-target asthma drugs, because the pleiotropic anti-inflammatory signaling actions of NO2-FA are expected to strike a pharmacological chord, rather than a note, in this complex inflammatory phenotype.